The present invention relates to pharmaceutical agents (compounds) which act as leukotriene B.sub.4 (LTB.sub.4) synthesis inhibitors in mammals. The compounds inhibit LTB.sub.4 synthesis by inhibiting phospholipase A.sub.2 (PLA.sub.2) activity. PLA.sub.2 is an important enzyme in the biosynthesis of leukotrienes as PLA.sub.2 acts to release arachidonic acid from phospholipids. Once released, arachidonic acid is rapidly metabolized by a variety of enzymes of the arachidonic acid cascade to produce prostaglandins, leukotrienes and related compounds. The use of the compounds herein to inhibit PLA.sub.2 activity thus inhibits the release of arachidonic acid from phospholipids. The inhibition of release of arachidonic acid similarly diminishes subsequent products in the arachidonic acid cascade, such as prostaglandins, leukotrienes, and related compounds, including LTB.sub.4.
LTB.sub.4 (Formula I) is an arachidonic acid metabolite which is produced by the 5-lipoxygenase pathway. Pharmacologically, LTB.sub.4 is an important mediator of ##STR2## inflammation. LTB.sub.4 is known to induce chemotaxis, chemokinesis, aggregation, and degranulation of leukocytes in vitro, and to induce accumulation of polymorphonuclear leukocytes, and increase vascular permeability and edema formation in vivo. Particularly high levels of LTB.sub.4 are detected in lesions in inflammatory diseases such as rheumatoid or spondylarthritis, gout, psoriasis, ulcerative colitis, Crohn's disease, multiple sclerosis and some respiratory diseases. Since the compounds herein inhibit PLA.sub.2 and thereby LTB.sub.4 synthesis, the compounds of the present invention are useful in treating inflammatory conditions in mammals such as psoriasis, Crohn's disease, ulcerative colitis, multiple sclerosis and the like.
Accordingly, it is an object of this invention to produce compounds for use as pharmaceutical agents which will exhibit LTB.sub.4 inhibitory activity in mammals.
The pharmacology of the biologically active leukotrienes is generally discussed in J. Clin. Invest. 73, 889-897 (1984).
SUMMARY OF THE INVENTION
This invention relates to a compound of the formula: ##STR3## or a pharmaceutically acceptable salt thereof wherein X is oxygen, sulfur, --CH.dbd.CH--, or --CH.dbd.N--;
wherein R.sup.1 is --CO.sub.2 R.sup.2 or tetrazole; PA0 wherein R.sup.2 is hydrogen, alkyl of 1 to 6 carbons or a pharmaceutically acceptable cation; PA0 wherein R is an alkyl of from 1 to 20 carbons, --(CH.sub.2).sub.p CF.sub.3 or --(CH.sub.2).sub.q R.sup.3 wherein R.sup.3 is alkoxy, phenoxy or alkoxy substituted phenoxy wherein the alkoxy group has from 1 to 8 carbons; PA0 wherein p and q are integers from 0 to 20; PA0 wherein n is 0 or 1; and PA0 wherein m is 0, 1, 2, or 3. PA0 wherein R.sup.1 is --CO.sub.2 R.sup.2 or tetrazole; PA0 wherein R.sup.2 is hydrogen, alkyl of 1 to 6 carbons or a pharmaceutically acceptable cation; PA0 wherein R is an alkyl of from 1 to 20 carbons, --(CH.sub.2).sub.p CF.sub.3 or --(CH.sub.2).sub.q R.sup.3 wherein R.sup.3 is alkoxy,phenoxy or alkoxy substituted phenoxy wherein the alkoxy group has from 1 to 8 carbons; PA0 wherein p and q are integers from 0 to 20; PA0 wherein n is 0 or 1; and PA0 wherein m is 0, 1, 2, or 3. PA0 wherein R.sup.1 is --CO.sub.2 R.sup.2 or tetrazole; PA0 wherein R.sup.2 is hydrogen, alkyl of 1 to 6 carbons or a pharmaceutically acceptable cation; PA0 wherein R is an alkyl of from 1 to 20 carbons, --(CH.sub.2).sub.p CF.sub.3 or --(CH.sub.2).sub.q R.sup.3 wherein R.sup.3 is alkoxy, phenoxy or alkoxy substituted phenoxy wherein the alkoxy group has from 1 to 8 carbons; PA0 wherein p and q are integers from 0 to 20; PA0 wherein n is 0 or 1; and PA0 wherein m is 0, 1, 2, or 3. PA0 wherein R.sup.1 is --CO.sub.2 R.sup.2 or tetrazole; PA0 wherein R.sup.2 is hydrogen, alkyl of 1 to 6 carbons or a pharmaceutically acceptable cation; PA0 wherein R is an alkyl of from 1 to 20 carbons, --(CH.sub.2).sub.p CF.sub.3 or --(CH.sub.2).sub.q R.sup.3 wherein R.sup.3 is alkoxy, phenoxy or alkoxy substituted phenoxy wherein the alkoxy group has from 1 to 8 carbons; PA0 wherein p and q are integers from 0 to 20; PA0 wherein n is 0 or 1; and PA0 wherein m is 0, 1, 2, or 3.
This invention, more specifically, relates to a compound of the formula: ##STR4## or a pharmaceutically acceptable salt thereof wherein X is oxygen, sulfur, --CH.dbd.CH--, or --CH.dbd.N--;
This invention also relates to a compound of the formula: ##STR5## or a pharmaceutically acceptable salt thereof wherein X is oxygen, sulfur, --CH.dbd.CH--, or --CH.dbd.N--;
This invention also relates to a compound of the formula: ##STR6## or a pharmaceutically acceptable salt thereof wherein X is oxygen, sulfur, --CH.dbd.CH--, or --CH.dbd.N--;